17-estradiol (E2) retards/prevents the development and progression of glomerulosclerosis (GS) in female mice, a disease process, which is largely determined by, age, genetic traits, and sex. E2 exposure maintains glomerular cells in an estrogen responsive/sensitive state. Prolonged estrogen deficiency leads to estrogen unresponsiveness at which time E2 replacement no longer reduces GS. It is generally accepted that aging is associated with an increase in oxidant stress (OS), which promotes age-related diseases especially in the cardiovascular/renal systems, including the glomerulus. Another feature of aging in female individuals is the loss of E2-mediated cardiovascular/renal protection. Mitochondria are a major source of reactive oxygen species (ROS), and the production and action of ROS can be modulated by E2. Based on new preliminary data, we hypothesize that E2 action modulates OS, which directly affects maintenance or deterioration of glomerular structure and function. We postulate that (i) OS increases in states of and/or as a result of E2 deficiency which promotes the development and progression of GS during aging, (ii) E2 replacement after prolonged periods of estrogen deficiency fails to reverse or prevent progression of GS because of the lost ability of E2 to restore its protective effects against OS in glomerular cells, and (iii) E2-mediated actions modulate mitochondrial respiration, oxidative phosphorylation, apoptosis and retrograde signaling pathways. We propose the following Specific Aims to test this hypothesis: Aim I, Determine whether OS diminishes estrogen-mediated protection in mesangial cells and podocytes during aging; Aim II, Determine if estrogen action modulates mitochondrial oxidative phosphorylation, respiration, apoptosis and retrograde signaling in mesangial cells and podocytes during aging. Aim III, Determine whether glomerular-cell specific deletion of ERa in young female B6 mice leads to GS similar to that seen in aging and whether OS plays a role in vivo. PUBLIC HEALTH RELEVANCE: Age-associated renal disease presents an important health problem, since 11% of those 65 years or older have decreased renal function, even when corrected for hypertension and diabetes mellitus. Estrogen deficiency contributes to the development of renal disease in aging women. This proposal will elucidate the role of the age-related decrease of estrogen action and the increase of oxidant stress in the development of renal disease in aging women.